Sirolimus, also known as rapamycin, an immunosuppressant drug used to prevent rejection in organ transplantation. It is especially useful in kidney transplants.
Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. Chemically, it is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-pentone, having a structure of Formula I.

U.S. Pat. Nos. 5,100,899, 5,212,155, 5,308,847 and 5,403,833 disclose methods of inhibiting transplant rejection in mammals using sirolimus and derivatives and prodrugs thereof.
U.S. Pat. No. 5,145,684 discloses dispersible particles consisting essentially of a crystalline drug substance having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400 nm and methods for the preparation of such particles and dispersions containing these particles.
U.S. Pat. Nos. 5,516,770 and 5,530,006 disclose intravenous sirolimus formulations.
U.S. Pat. Nos. 5,536,729 and 5,559,121 disclose liquid oral sirolimus formulations.
U.S. Pat. Nos. 5,989,591 and 5,985,325 disclose a solid dosage unit of sirolimus comprising a core and a sugar overcoat, said sugar overcoat comprising sirolimus, one or more surface modifying agents, one or more sugars, and optionally one or more binders.
Sirolimus is marketed by Wyeth under the trade name Rapamune® as 0.5 mg, 1 mg and 2 mg oral tablets for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. It is also available as an oral solution containing 1 mg/ml sirolimus.
Sirolimus is described as BCS Class 2 drug in Pharmaceutical Research, Vo. 22, No. 1, January 2005 by Chi-Yuan Wu et al. Because of its poor water and oil solubility, only few formulations of rapamycin have proven satisfactory. Rapamycin is stable but not bioavailable if it is a crystalline solid with large particle size. Further, rapamycin is bioavailable but not stable as a micronized material. Hence, the challenge was to design a bioavailable and stable solid oral dosage form of rapamycin. The solution to this as known in the art as of today is nanonization of rapamycin by means of nanotechnology and to stabilize the nanosized particles and thereby develop a stable and bioavailable solid oral dosage form.
Nanonization of poorly soluble drug is a complex process and requires additional step during manufacturing. Nanonization increases the surface area available for dissolution; however, it also increases the change in free energy of the system when exposed to an aqueous solution. This results in particle aggregation and decreases the dissolution rate. Also, very fine nanosized particles are difficult to handle due to static charge that develops on particle surface during processing.
Moreover, sirolimus is known to have poor oil and water solubility. It is rapidly but poorly absorbed following oral administration with an approximate oral bioavailability of 15%. It reaches maximum blood concentrations in 0.5-2.3 hours after dosing. However oral formulations of rapamycin have restrictions due to their low solubility.
There is therefore an existing and continual need for stable and therapeutically equivalent oral solid pharmaceutical compositions of sirolimus. The compositions of the invention overcome all the encountered problems exemplified above.